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Heme Oxygenase-1 in Gastrointestinal Tract Health and Disease

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Heme Oxygenase-1 in Gastrointestinal Tract Health and Disease antioxidants Review Heme Oxygenase-1 in Gastrointestinal Tract Health and Disease 1,2, 3 4, 1,5, , Jose D. Puentes-Pardo * , Sara Moreno-SanJuan , Ángel Carazo y and Josefa León * y 1 Research Unit, Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain 2 Department of Pharmacology, Faculty of Pharmacy, University of Granada, 18011 Granada, Spain 3 Cytometry and Microscopy Research Service, Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain; [email protected] 4 Genomic Research Service, Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain; [email protected] 5 Clinical Management Unit of Digestive Disease, San Cecilio University Hospital, 18016 Granada, Spain * Correspondence: [email protected] (J.D.P.-P.); [email protected] (J.L.); Tel.: +34-958-023-706 (J.L.) These authors contributed equally to this work. y Received: 28 October 2020; Accepted: 29 November 2020; Published: 2 December 2020 Abstract: Heme oxygenase 1 (HO-1) is the rate-limiting enzyme of heme oxidative degradation, generating carbon monoxide (CO), free iron, and biliverdin. HO-1, a stress inducible enzyme, is considered as an anti-oxidative and cytoprotective agent. As many studies suggest, HO-1 is highly expressed in the gastrointestinal tract where it is involved in the response to inflammatory processes, which may lead to several diseases such as pancreatitis, diabetes, fatty liver disease, inflammatory bowel disease, and cancer. In this review, we highlight the pivotal role of HO-1 and its downstream effectors in the development of disorders and their beneficial effects on the maintenance of the gastrointestinal tract health. We also examine clinical trials involving the therapeutic targets derived from HO-1 system for the most common diseases of the digestive system. Keywords: heme oxygenase; gastrointestinal tract; cancer; diabetes; pancreatitis; inflammatory bowel disease; peptic ulcer disease; fatty liver disease; ferroptosis 1. Introduction Heme oxygenase (HO) is the enzyme that catalyzes the first and the rate-limiting step of heme oxidative degradation. During this reaction, HO requires NADPH and oxygen to degrade heme, releasing carbon monoxide (CO), free iron (Fe2+), and biliverdin, which is reduced to bilirubin by biliverdin reductase consuming another NADPH molecule, as by-products [1,2]. Three different isoforms have been described to the date, heme oxygenase 1 (HO-1), which is an inducible form in response to diverse chemical and physical stimuli; heme oxygenase 2 (HO-2) which is the constitutive form expressed throughout the body, but specifically in testes, endothelial cells and brain; and heme oxygenase 3 (HO-3), a poor catalytically-active form only found in rats [3,4]. Bacterial HO-like proteins have also been described, pointing out the evolutionary conserved activity of this enzyme through evolution, and has been postulated that gut microbiota may take part somehow in heme metabolism [5]. Despite of the existence of two active isoforms, most of the research has been focus on HO-1, since HO-1 knock-out animals present a highly intrauterine death ratio and overall severe chronic inflammation, accompanied by a predisposition to oxidative stress and iron metabolism dysfunction [6–9]. Meanwhile, HO-2 knockout models remain fertile and show less severe disturbances, mainly localized to those tissues in which HO-2 is higher expressed, such as the nervous system [10]; Antioxidants 2020, 9, 1214; doi:10.3390/antiox9121214 www.mdpi.com/journal/antioxidants Antioxidants 2020, 9, 1214 2 of 30 or even being positive under certain conditions like intracerebral hemorrhage [11]. In humans, there are only two described cases of HO-1 deficiency: A 6-year-old boy who suffered from hemolytic anemia, growth retardation, leukocytosis, elevated heme in serum, low serum bilirubin levels, and iron depositions throughout the body; and a 15-year-old girl who shared similar symptoms including severe hemolysis, inflammation, nephritis, and premature death [12,13]. HO-1 is expressed at relatively-low basal levels in all mammalian tissues but is up-regulated under stress conditions. However, this inducible form occurs at high levels in spleen macrophages [14] and Kupffer cells in the liver [15], due to its role in senescent red blood cells clearance, as well as in hematopoietic stem cells in the bone marrow to control the levels of heme, which is an erythroid differentiation factor [16]. At the cellular level, HO is anchored to the endoplasmic reticulum through a C-terminal transmembrane region facing the cytosol [17], although some evidences have shown that HO-1 can be translocated to mitochondria in lung and gastric epithelial cells, where is associated with a protective role [18,19]. Intriguingly, nuclear localization of HO-1 has also been described. Under stress conditions, HO-1 may be translocated to the nucleus, where it exerts non-enzymatic functions, regulating its own expression, as well as transcriptional factors related to oxidative stress responses, which might be in turn associated with cancer progression [20]. HO-1 is considered as both a potent anti-oxidative and a cytoprotective agent. These activities are exerted, respectively, by two different but synergic mechanisms: (1) The removal of heme group, which is a potent oxidative agent leading to generation of reactive oxygen species (ROS) [21]; and (2) as a result of multiple mechanism underpinning by its by-products CO, biliverdin/bilirubin and labile iron, which is not a direct action of its enzymatic activity [16]. Indeed, HO-1 induction and/or impairment has been associated with a huge variety of diseases such as cancer [20], neurodegenerative, and cardiovascular diseases [22,23], among others. Apart from the spleen and liver, HO-1 levels also seem to be constitutively expressed at the gastrointestinal system [24]. Since the digestive system is continuously exposed to a wide variety of stress conditions, the HO system seems to play an important part in gastrointestinal tract health and disease. In this review we summarize the essential role of HO-1 and its end-products for ensuring the gastrointestinal tract health and how its dysfunction lead to several disorders of the esophagus, stomach, pancreas, liver, and gut. We also examine the current ongoing clinical trials exploring the therapeutic targets derived from the HO-1 system for the most common gastrointestinal diseases. 2. Molecular Regulation of HO-1 Expression The regulation of HO-1 expression is mainly exerted at transcriptional level. HO-1 is encoded by the HMOX1 gene located on chromosome 22q12.3. It has five exons, four introns and three regulatory regions, one proximal ( 0.3 Kb) and two distals from the promoter region (E1 at 4 kb and − − E2 at 10 kb) [25,26]. These regulatory regions contain diverse transcriptional factor binding sites − (hypoxia-inducible factor 1 (HIF-1), nuclear factor kappa B (NF-κB), activator protein (AP-1) binding sites), stress responses elements (StRE), metal response elements (MtRE), and heat shock consensus (HSE) sequences), which are involved in the tuning of the cellular redox state [16,27]. This variety of regulatory elements allows the transcription of HMOX1 in response to a plethora of oxidative and inflammatory stimuli among which stand out its own substrate heme, heavy metals, radiations, ROS, growth factors, and cytokines [16]. Despite of the diversity of regulatory elements, the dominant sequence motif is the StRE, which behaves similar to Maf response element (MARE) and the antioxidant response element (ARE) [28,29]. In consequence, among the different transcriptional factors, the nuclear erythroid 2-related factor (Nrf2) and Bach1 exert a pivotal role in HMOX1 regulation, activating or repressing, respectively, its transcription [29]. Under physiological conditions Nrf2, a basic leucine zipper protein, is retained into the cytoplasm by the Kelch-like ECH-associated protein (Keap-1), which inhibits its translocation to the nucleus [30]. Keap-1 forms a heterodimer with Nrf2, sequestering and facilitating the Nrf2 targeting and ubiquitination by Cullin-RING E3 ubiquitin ligase complex for proteosomal degradation [30,31]. Antioxidants 2020, 9, 1214 3 of 30 Antioxidants 2020, 9, x FOR PEER REVIEW 3 of 31 InIn parallel, parallel, Bach1 Bach1 is translocatedis translocated to theto the nucleus nucleus where where it heterodimerizes it heterodimerizes to formto form a complex a complex with with small Mafsmall protein, Maf protein, and then, and the then, Bach1 the/small Bach1/small Maf complex Maf complex binds tobinds StRE, to StRE, repressing repressing HO-1 HO-1 expression expression [32,33 ] (Figure[32,33]1). (Figure 1). FigureFigure 1. 1. SchemeScheme of of the the transcriptional transcriptional regulation regulation of HMOX1 of HMOX1. The .HMOX1 The HMOX1 gene regulatorygene regulatory region regioncontains contains several several stress stress response response elements elements (StR (StRE)E) to which to which transcription transcription factors factors binds. binds. Under Under physiologicalphysiological conditions, conditions, thethe nuclearnuclear erythroid erythroid 2-related 2-related factor factor (Nrf2) (Nrf2) is sequestered is sequestered in the in nucleus the nucleus by bythe the Kelch-like Kelch-like ECH-associated ECH-associated protein protein (Keap-1), (Keap-1), forming forming a aheterodimer heterodimer and and targeting targeting Nrf2 Nrf2 for for ubiquitinationubiquitination
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